Fuller R W, Snoddy H D
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Biochem Pharmacol. 1993 Jun 9;45(11):2355-8. doi: 10.1016/0006-2952(93)90212-f.
The i.p. injection of R-fluoxetine into mice at doses of 1-10 mg/kg led to higher concentrations of the desmethyl metabolite, R-norfluoxetine, in whole brain than was true for S-fluoxetine. R-Norfluoxetine, but not S-norfluoxetine, concentrations predominated over those of the parent drug at 7-24 hr after injection of the corresponding fluoxetine enantiomer. The more rapid N-demethylation of R-fluoxetine, and the relative inactivity of R-norfluoxetine as a serotonin uptake inhibitor compared with S-norfluoxetine, may explain the earlier report that R-fluoxetine is less potent than S-fluoxetine in antagonizing p-chloroamphetamine depletion of brain serotonin in mice. In the present study, a 10 mg/kg, i.p., dose of S-fluoxetine completely prevented p-chloroamphetamine given 24 hr later from depleting brain serotonin, whereas R-fluoxetine offered no protection at this time.
以1-10毫克/千克的剂量给小鼠腹腔注射R-氟西汀，导致全脑中去甲基代谢物R-去甲氟西汀的浓度高于S-氟西汀。在注射相应的氟西汀对映体后7-24小时，R-去甲氟西汀而非S-去甲氟西汀的浓度超过了母体药物的浓度。R-氟西汀更快速的N-去甲基化，以及与S-去甲氟西汀相比R-去甲氟西汀作为5-羟色胺摄取抑制剂的相对无活性，可能解释了早期的报告，即R-氟西汀在拮抗对氯苯丙胺对小鼠脑5-羟色胺的耗竭方面比S-氟西汀效力更低。在本研究中，腹腔注射10毫克/千克剂量的S-氟西汀可完全防止24小时后给予的对氯苯丙胺耗尽脑5-羟色胺，而此时R-氟西汀则没有保护作用。
